The Journal of Experimental Medicine
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Published online 15 May 2000.
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© The Rockefeller University Press, 0022-1007/2000/5/1755/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 10, May 15, 2000 1755-1764

Original Article

A Key Role for Cc Chemokine Receptor 4 in Lipopolysaccharide-Induced Endotoxic Shock

Yolande Chvatchkoa, Arlene J. Hoogewerfa, Alexandra Meyera, Sami Alouania, Pierre Juillarda, Raphaele Busera, Francois Conqueta, Amanda E.I. Proudfoota, Timothy N.C. Wellsa, and Christine A. Powera

a Serono Pharmaceutical Research Institute, 1228 Plan-les-Ouates/Geneva, Switzerland
Serono Pharmaceutical Research Institute, 14, chemin des Aulx, 1228 Plan-les-Ouates/Geneva, Switzerland.41-22-7069-71841-22-7069-666

yolande.chvatchko{at}serono.com

CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), is expressed in the thymus and spleen, and also by peripheral blood T cells, macrophages, platelets, and basophils. Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4–/–) mice by gene targeting. CCR4–/– mice developed normally. Splenocytes and thymocytes isolated from the CCR4–/– mice failed to respond to the CCR4 ligands TARC and MDC, as expected, but also surprisingly did not undergo chemotaxis in vitro in response to macrophage inflammatory protein (MIP)-1{alpha}. The CCR4 deletion had no effect on Th2 differentiation in vitro or in a Th2-dependent model of allergic airway inflammation. However, CCR4–/– mice exhibited significantly decreased mortality on administration of high or low dose bacterial lipopolysaccharide (LPS) compared with CCR4+/+ mice. After high dose LPS treatment, serum levels of tumor necrosis factor {alpha}, interleukin 1β, and MIP-1{alpha} were reduced in CCR4–/– mice, and decreased expression of MDC and MIP-2 mRNA was detected in peritoneal exudate cells. Analysis of peritoneal lavage cells from CCR4–/– mice by flow cytometry also revealed a significant decrease in the F4/80+ cell population. This may reflect a defect in the ability of the CCR4–/– macrophages to be retained in the peritoneal cavity. Taken together, our data reveal an unexpected role for CCR4 in the inflammatory response leading to LPS-induced lethality.

Key Words: CC chemokine receptor 4 • lipopolysaccharide • endotoxic shock • F4/80 antigen • T helper type 2 cells

Abbreviations used in this paper: BAL, bronchoalveolar lavage; BALF, BAL fluid; BHR, bronchial hyperreactivity; CCR, CC chemokine receptor; D-gal, D-galactosamine; ES, embryonic stem; MCh, methacholine; MDC, macrophage-derived chemokine; MIP, macrophage inflammatory protein; Penh, enhanced pause; RANTES, regulated upon activation, normal T cell expressed and secreted chemokine; RT, reverse transcriptase; TARC, thymus and activation-regulated chemokine; Tlr4, Toll-like receptor 4.

A.J. Hoogewerf's present address is The Midland Certified Reagent Company, 3112-A West Cuthbert Ave., Midland, TX 79701.

F. Conquet's present address is Glaxo Wellcome Experimental Research, Institut de Biologie Cellulaire et de Morphologie, CH-1005 Lausanne, Switzerland.

© 2000 The Rockefeller University Press


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